This invention relates to modeling systems generally, and particularly to computer-based simulation systems used in determining three-dimensional structures (tertiary native conformations) of globular protein molecules.
The value of determining structure or conformation of proteins is well known. For example, in 1961 a Nobel Prize was awarded to Max Perutz for his work in determining the structure of the hemoglobin protein in blood. From this discovery, we now understand more about sickle cell hemoglobin and how drugs can be designed to treat patients with this disorder.
The prediction of antigenic determinants also is based on the prediction of protein tertiary structure. One such scientific work is reported, for example, by Hopp and Woods in "Prediction of protein antigenic determinants from amino acid sequences", Proceedings of the National Academy of Science USA 78, pp. 3824-3828 (1981), and in "A Computer Program for Predicting Protein Antigenic Determinants", Molecular Immunology Vol. 20, No. 4, pp. 483-489 (1983).
The structure (native conformation) of the protein, particularly the conformation of the outer sites or sidechains (which are linked to the backbone and inner structures of the protein) often determines the capacity of the protein to interact with other proteins. One factor which directly influences conformation is protein folding. Deciphering the rules through which the building blocks (amino acid sequences) of the protein affect folding promises significant improvements in the design of proteins, many with a host of new catalytic functions useful, for example, in the chemical, food processing, pharmaceutical, and other industries.
As a tool, computer systems are sometimes used to combine and display protein structures. One such system, used to convert two polypeptide chains to a single polypeptide chain, is described for example in U.S. Pat. No. 4,704,692, entitled "Computer Based System and Method for Determining and Displaying Possible Chemical Structures for Converting Double- or Multiple-Chain Polypeptides to Single-Chain Polypeptides", issued Nov. 3, 1987 to inventor Robert C. Ladner. Computer systems have also been used to investigate protein structures and predict protein folding. A few of such uses have been reported in Protein Folding by N. Go et al., pp. 167-81, ed. by N. Jaenicke, Amsterdam, Holland (1980); Biopolymers by S. Miyazawa et al., 21:1333-63, (1982); and Journal of Molecular Biology, by M. Levitt, 104:59-107 (1976).
These systems often (a) cannot process a full sequence of amino acid residues of a protein or protein segment (i.e., cannot process or otherwise represent the interactions of all the residues of the protein or protein segment; this task often becomes intractable, the system generally becomes unduly burdened by the many degrees of freedom of the residues), (b) cannot complete the folding process (because of inability of the system to recognize false, local energy--minima conditions), (c) cannot represent tertiary conformations in three dimensions, (d) cannot represent interactions between sidechains, (e) do not display the pathway taken by a protein in folding, or (f) do not permit free (unconstrained) interactions between residues for more realistic simulation of real proteins.
What is needed and would be useful, therefore, is a computer-based system that would eliminate the above-mentioned deficiencies, and provide a faster way of determining protein structures, thereby increasing the productivity of many scientists and encouraging the undertaking of many more needed investigations, including investigation of structures of protein sequences obtained from mapping of the human genome.